ADRB2
Beta-2 adrenergic receptor (Beta-2 adrenoreceptor) (Beta-2 adrenoceptor) [ADRB2R] [B2AR]
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Existing literature indicates that ADRB2 gene is associated with health and longevity, but none of previous studies investigated associations of carrying the ADRB2 minor alleles and interactions between ADRB2 genotypes and social/behavioral factors(GxE) with health outcomes at advanced ages. This study intends to fill in this research gap. We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90 . To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods. Interaction between regular exercise and carrying rs1042718 minor allele is significantly and positively associated with good cognitive function; interaction between regular exercise and carrying rs1042718 or rs1042719 minor allele is significantly and positively associated with self-reported good health; and interaction between social-leisure activities and carrying rs1042719 minor allele is significantly and positively associated with self-reported good health. Carrying rs1042718 or rs1042719 minor alleles is significantly and negatively associated with negative emotion, but the ADRB2 SNPs are not significantly associated with cognitive function and self-reported health. Our structural equation analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular exercise and social-leisure activities with cognitive function and self-reported health, and negative association of negative emotion with cognitive function, were much stronger among carriers of rs1042718 or rs1042719 alleles, compared to the non-carriers. The results indicate significant positive associations of interactions between social/behavioral factors and the ADRB2 genotypes with health outcomes of cognitive function and self-reported health, and negative associations of carrying rs1042718 or rs1042719 minor alleles with negative emotion, at advanced ages in China. Our findings are exploratory rather than causal conclusions. This study implies that near-future health promotion programs considering individuals' genetic profiles, with appropriate protection of privacy/confidentiality, would yield increased benefits and reduced costs to the programs and their participants.
MeSH Terms
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- China
- Female
- Genotype
- Health Status
- Health Surveys
- Humans
- Longitudinal Studies
- Male
- Receptors, Adrenergic, beta-2
- Social Behavior
The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (ADRB2) have been associated with cognitive function and brain white matter integrity. The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was N = 686-765, and for neuroimaging variables was N = 488-587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with ADRB2 variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between ADRB2, cognitive function and brain white matter integrity is required.
MeSH Terms
- Aged
- Aging
- Alleles
- Brain
- Cognition
- Cognition Disorders
- Cohort Studies
- Diffusion Magnetic Resonance Imaging
- False Positive Reactions
- Female
- Genetic Variation
- Genotype
- Humans
- Male
- Mutation
- Nerve Fibers, Myelinated
- Phenotype
- Receptors, Adrenergic, beta-2
- Scotland
β-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of β-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the β-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography-matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.00053-0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long-lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17-1.88, P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51-0.78, P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the β2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared with C-G (P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of β2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.
MeSH Terms
- Adenylyl Cyclases
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Case-Control Studies
- Female
- Follow-Up Studies
- Genes, Reporter
- HEK293 Cells
- Haplotypes
- Humans
- Linkage Disequilibrium
- Longevity
- Luciferases, Renilla
- Male
- Mitogen-Activated Protein Kinase 1
- Polymorphism, Single Nucleotide
- Protein Biosynthesis
- Receptors, Adrenergic, beta-1
- Receptors, Adrenergic, beta-2
- Surveys and Questionnaires
- Transfection
The Gln(27)Glu polymorphism but not the Arg(16)Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln(27)Gln genotype increases risks of cancer, MI and IC, whereas the Glu(27) allele or, equivalently, the Gly(16)Glu(27) haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln(27) allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Alleles
- Amino Acid Substitution
- Cardiovascular Diseases
- Child
- Child, Preschool
- Evolution, Molecular
- Female
- Health
- Humans
- Longevity
- Male
- Middle Aged
- Polymorphism, Genetic
- Receptors, Adrenergic, beta-2
- Risk
- Young Adult
It has recently been reported that the evolutionarily ancestral alleles of two functional polymorphisms in the beta(2)-adrenergic receptor gene (ADRB2) were related to higher cognitive ability in the 70 year old participants of the Lothian Birth Cohort 1936 (LBC1936). One emerging important factor in cognitive aging is the integrity of white matter tracts in the brain. Here, we used diffusion tensor MRI-based tractography to assess the integrity of eight white matter tracts in a subsample of the LBC1936. Higher integrity of the splenium of the corpus callosum predicted better cognitive ability in old age, even after controlling for IQ at age 11. Also, the ancestral allele of one ADRB2 SNP was associated with both splenium integrity and better cognitive aging. While the effects of the SNP and splenium integrity on cognitive aging were largely independent, there was some evidence for a partial mediation effect of ADRB2 status via splenium integrity.
MeSH Terms
- Aged
- Aging
- Brain
- Cognition
- Cohort Studies
- Corpus Callosum
- Female
- Genomics
- Genotype
- Humans
- Male
- Middle Aged
- Models, Genetic
- Neuropsychological Tests
- Polymorphism, Genetic
- Receptors, Adrenergic, beta-2
Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior.
MeSH Terms
- Adult
- Aging
- Animals
- Brain
- Child
- Evolution, Molecular
- Family
- Female
- Genome, Human
- Humans
- Intelligence
- Male
- Pan troglodytes
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Primates
- Proteins
- Receptors, Adrenergic, beta-2
- Regression Analysis
- Rodentia
- Selection, Genetic
The human trabecular meshwork and ciliary body, which express beta-adrenergic receptors (ADRB1 and ADRB2), control aqueous humor dynamics. We investigated associations of ADRB polymorphisms with open-angle glaucoma (OAG), because ADRB gene polymorphisms alter receptor function. We studied 240 Japanese controls and 505 Japanese OAG patients including 211 with primary open-angle glaucoma (POAG), and 294 with normal-tension glaucoma (NTG). Associations of four polymorphisms (Ser49Gly and Arg389Gly in the ADRB1 gene; Arg16Gly and Gln27Glu in the ADRB2 gene) were compared between patients and controls. Age, intraocular pressure (IOP), and visual field defects at diagnosis were examined for associations with polymorphisms. The Arg389Gly polymorphism in the ADRB1 gene showed significantly different allele and genotype frequencies in patients with NTG than in controls (p = 0.004 and 0.006, respectively). Other polymorphisms did not show a significant frequency difference. In POAG patients, carriers of Gly16 in the ADRB2 gene were significantly younger at diagnosis than noncarriers (p<0.001). The IOP at diagnosis was significantly higher in OAG patients carrying 27Glu in the ADRB2 gene than in patients without this allele (p<0.001). Clinical characteristics of OAG patients did not differ significantly in relation to other polymorphisms. Certain polymorphisms of the ADRB1 and ADRB2 genes influence the pathophysiology of OAG in Japanese patients.
MeSH Terms
- Aged
- Aging
- Asian Continental Ancestry Group
- Case-Control Studies
- Female
- Gene Frequency
- Genes, Dominant
- Genes, Recessive
- Genetic Predisposition to Disease
- Genotype
- Glaucoma, Open-Angle
- Heterozygote
- Humans
- Intraocular Pressure
- Male
- Middle Aged
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Receptors, Adrenergic, beta-1
- Receptors, Adrenergic, beta-2
Few studies have examined to what extent genetic variants of the beta2-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although beta2-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm-based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (P=0.01). Haplotype 1 was associated with protection against hypertension in young (< or =50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; P=0.02). This age-specific effect was further supported by the observations that young subjects carrying > or =1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (P<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; P<0.05) and decreased heart rate (7%; P<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.
MeSH Terms
- Adult
- African Americans
- Aging
- Blood Pressure
- Body Mass Index
- European Continental Ancestry Group
- Female
- Gene Dosage
- Genetic Predisposition to Disease
- Genotype
- Haplotypes
- Heart Rate
- Heterozygote
- Humans
- Hypertension
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Receptors, Adrenergic, beta-2